Delivery system comprising two sections for delivering somatotropin

ABSTRACT

A delivery system is disclosed for delivering a beneficial agent to an animal. The delivery system comprises a wall that surrounds a lumen, said wall comprising a composition that limits the passage of fluid into the system and a composition that permits the passage of fluid into the system. The lumen comprises a beneficial agent and an expandable member. The delivery system comprises an exit means for delivering the beneficial agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. Ser. No. 07/283,359 filed on Dec.13, 1988, which application is incorporated herein by reference, andbenefit is claimed of its filing date. These applications are assignedto the ALZA Corporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to both a novel and to an unobvious deliverysystem. More particularly, the invention relates to a delivery systemcomprising (1) housing means, (2) a compartment, and (3) exit means. Thehousing means comprises (a) a section that substantially restricts theingress of fluid into the delivery system, and (b) a section thatpermits the ingress of fluid into the delivery system. The compartmentcomprises (c) a bioavailable and biocompatible beneficial agentformulation and (d) means for delivering the agent formulation from thedelivery system. The exit means comprises (e) at least one passageway inthe housing means for connecting the exterior with the interior of thedelivery system for delivering the agent formulation from the deliverysystem.

BACKGROUND OF THE INVENTION

Delivery systems for administering a beneficial agent to a biological,fluid environment of use are known to the prior art. For example, U.S.Pat. No. 3,845,770 issued to Theeuwes and Higuchi, and in U.S. Pat. No.3,916,899 issued to the same patentees, a device is disclosed comprisinga wall that surrounds a compartment containing a beneficial agent. Thewall is permeable to the passage of fluid and comprises a passagewaythat is preformed or formed during use through the wall for deliveringthe beneficial agent from the device. The devices of these patentsrelease the beneficial agent by fluid being imbibed through the wallinto the compartment at a rate determined by the permeability of thewall and the osmotic pressure gradient across the wall. The fluidimbibed into the device mixes with the beneficial agent to form anaqueous solution comprising the beneficial agent that is dispensedthrough the passageway from the device. The devices of these patents areextraordinarily effective for delivering a beneficial agent that isstable and soluble in aqueous and biological fluids and exhibits anosmotic pressure gradient across the wall against the fluid. The devicesare effective also for delivering a beneficial agent that is mixed withan osmotically effective solute soluble in fluid that exhibits anosmotic pressure gradient across the wall against an aqueous fluid.

A further advancement in the delivery art for dispensing a stableformulation is disclosed in U.S. Pat. No. 3,995,632 issued to Nakano,Higuchi and Hussain. The dispenser disclosed in this patent dispenses astable composition that absorbs heat and forms a dispensable melt. Themelt is dispensed by a solution of magnesium sulfate increasing involume and occupying the space originally occupied by the melt.

A quantum improvement in osmotic devices was presented to thepharmaceutical dispensing art by inventor Theeuwes in U.S. Pat. Nos.4,111,202; 4,111,203; and 4,203,439. In these patents the deliverykinetics of the devices were enhanced for delivering a beneficial agentwith different degrees of solubility in an aqueous-type fluid. Thekinetics were improved by manufacturing the devices with a beneficialagent compartment separated by a film from an osmotic compartment. Thedevices deliver the beneficial agent by fluid being imbibed through thewall into the osmotic compartment to fill the compartment with fluidthat acts as a driving force and causes the film to move. The film movesagainst the beneficial agent compartment and the driving force pushesthe beneficial agent through a passageway from the device.

A pioneer advancement in osmotic delivery devices was made by Corteseand Theeuwes in U.S. Pat. No. 4,327,725 and by Wong, Barclay, Deters andTheeuwes in U.S. Pat. No. 4,612,008. The devices disclosed in thesepatents comprise a semipermeable wall that surrounds a compartment. Thecompartment contains a beneficial agent formulation and a hydrogel.These devices operate by imbibing fluid into the compartment, wherein itcontacts the biological agent formulation and forms a dispensableaqueous formulation, and wherein it contacts the hydrogel causing it toexpand and push the dispensable aqueous formulation from the device.

The delivery devices described in the above patents operate successfullyfor their intended use and they can deliver many beneficial agents fortheir intended effects. Now, it has been observed their use can belimited because they lack the necessary elements to deliver beneficialagents that are sensitive to fluids, and to fluids containing biologicalgases. Their use may be limited because beneficial agents that aresensitive to such aqueous-biological fluids or to other fluids externalto the delivery device may be adversely affected by fluids that enterthe device and contact the beneficial agents during operation of thedevice. Examples of such fluid sensitive agents include proteins andpeptides, and hormones. Moreover, the prior art devices lack thenecessary means for their use as implant devices for dispensing suchsensitive agents to a biological fluid-rich environment of use.

It will be appreciated by those versed in the dispensing arts that if adelivery system is provided for administering at a controlled rate andfor protecting a beneficial agent that is sensitive to aqueous andbiological fluids, and which delivery system possesses the kineticability to deliver the protected beneficial agent in effective amountsover time, such a delivery system would have a positive value andrepresent an advancement in the dispensing arts. Likewise, it will beself-evident to those versed in the implant art that a pressing needexists for an implant that is essentially-free of the tribulationassociated with the prior art, and, that if such an implantable deliverysystem is provided, it would have a practical application in the fieldsof human and veterinary medicine and in the breeding and management offarm animals.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide adelivery system for delivering a beneficial agent that overcomes thelimitations associated with the prior art.

Another object of the invention is to provide a delivery system fordelivering in vivo a beneficial agent such as a drug that is difficultto deliver and now can be delivered by the delivery system intherapeutically effective amounts to both humans and livestock.

Another object of the invention is to provide a delivery systemcomprising means for protecting a beneficial agent from aqueous andbiological fluids.

Another object of the invention is to provide a delivery devicecomprising means for protecting a fluid sensitive biological agent inthe device from fluid, and means for administering the beneficial agentto an environment of use, wherein the environment of use may be a fluid,aqueous-biological environment.

Another object of the invention is to provide a delivery systemcomprising means for storing and for protecting a bioactive beneficialagent formulated in a biocompatible composition during its residency inthe delivery system.

Another object of the invention is to provide an implant for livestockthat can remain in the livestock until slaughter.

Another object of the invention is to provide a delivery systemcomprising means for high loading of a beneficial agent essentially-freefrom its inactivation while in the delivery system, and comprising meansfor delivering the beneficial agent at a controlled rate andcontinuously over time to a beneficial agent recipient.

Another object of the invention is to provide a delivery systemmanufactured as an osmotic therapeutic device comprising a beneficialagent, and which delivery system can administer a completepharmaceutical dosage regimen at a controlled rate continuously for aparticular time period, the use of which delivery system requiresintervention only for initiation and the possible termination of theregimen.

Another object of the invention is to provide a delivery system fordelivering a drug to an animal, including cattle and hogs, which term,"hogs," includes pigs and porcines, by using a delivery systemmanufactured as an osmotic device that possesses the ability to deliverthe beneficial drug over a broad range of dosage delivery ratesaccording to the predetermined time-release pattern to the biologicalrecipient over time.

Another object of the invention is to provide an osmotic devicecomprising a compartment containing a drug shielded from a fluidenvironment of use, and an expandable driving member that operates todiminish the volume occupied by the drug, thereby displacing and thusdelivering the drug from the device at a controlled rate over time.

Another object of the invention is to provide a delivery system fordelivering a dosage unit amount of a drug to a warm-blooded animal, suchas a ruminant or a swine, and which delivery system can be shaped, sizedand adapted as an implant for implanting it in the muscle tissue of ananimal, the subcutaneous space, the vaginal cavity, or in the peritonealcavity.

Another object of the invention is to provide an implantable,pharmaceutical delivery system for delivering a beneficial agent to ahuman or to a veterinary host, with the implant releasing the beneficialagent at a rate controlled by the implant, and when the release ofbeneficial agent is terminated abruptly, the implantable system leaves aminimal agent residue in the implant and in the host.

Another object of the invention is to provide an implantable deliverysystem that is implantable by using simple injection techniques and doesnot require extensive surgery for its placement in a biological tissue.

Another object of the invention is to provide an implant that can beplaced under the skin of an animal for releasing an effective amount ofa beneficial agent for causing the animal to gain weight at a greaterthan normal rate, and which implant remains intact and is easily andcompletely removed for allowing a withdrawal period prior to slaughter.

Another object of the invention is to provide a drug delivery devicethat is implantable, is compact in size and shape to allow easyplacement within the lumen of trocars and similar implanting orinjecting instruments that are limited in dimensions and, consequently,are essentially-free of undue trauma and discomfort to a receivinganimal.

Another object of the invention is to provide a delivery device shapedat its ends in a conical or spherical shape for reducing the forcenecessary to push the device into an implantation receiving site,thereby reducing the incidence of tissue damage and the incidence ofdamage to the delivery device, thereby enhancing the process ofimplantations.

Another object of the invention is to provide a delivery devicecomprising ends of a conical or spherical shape for producing a devicebetter designed to withstand elevated interior pressures occurringwithin the device during hydrodynamic pumping, which shape is of valuewhen the device is delivering high viscosity compositions that createhigher pressures during pumping at given flow rates and exit sizedpassageways.

Another object of the invention is to provide a delivery system that canbe placed under the skin of an animal for releasing an effective amountof a beneficial agent for causing increased productivity, whichincreases in productivity is a result of any combination of thefollowing, higher feed conversion efficiency as exemplified by a greaterration of animal weight gain to amount of feed intake, improved carcassquality as exemplified by a higher ratio of muscle tissue to fat tissue,and a higher than normal rate of animal weight gain.

Another objective of the invention is to provide a delivery device thatcompletely envelops the beneficial, fluid sensitive agent within theprotective polymer housing shaped conically or otherwise tapered about aclosed exit passageway that can be opened immediately prior toimplantation either manually or automatically by snapping-off, orcutting-off the thin tapered closed end, thereby maximizing the periodof protection offered by the sealed device and minimizing theopportunity for external environmental contamination of the beneficialagent housed within the device.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing art from the followingdetailed specification taken in conjunction with the accompanyingclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a view of a delivery system provided by the invention whereinthe delivery system comprises exit means formed during manufacture ofthe delivery system for delivering a beneficial agent to an environmentof use comprising a biological fluid;

FIG. 2 is a view of a delivery system provided by the invention, whichdelivery system is similar to the delivery system of FIG. 1, with thedelivery system of FIG. 2 comprising the added embodiment of an exitclosed by a break-off tip for preventing a premature delivery of abeneficial agent and for preventing contamination of a beneficial agenthoused within the delivery system prior to a force being applied to thebreak-off tip for forming an exit opening in the delivery system;

FIG. 3 is a view of a delivery system of the invention, wherein thedelivery system comprises another housing arrangement that provides alsomeans for protecting a beneficial agent sensitive to fluid from thefluid;

FIG. 4 is a view of another delivery system of the invention, whereinthe delivery system comprises a housing embracing a lead end with meansfor opening the delivery system that is structurally different than therear end;

FIG. 5 is an opened view of the delivery system of FIG. 1, illustratingone structural embodiment of the delivery system comprising a firstwalled section and a second walled section, with the delivery systemadditionally comprising a preformed manufactured exit passageway and adome shaped lead and rear end;

FIG. 6 is an opened view of the delivery system of FIG. 2 illustratingthe structure of the delivery system comprising a first and a secondwalled section, and a break-off tip that is easily broken-off at thetime of use for providing an exit passageway;

FIG. 7 is an opened view of a delivery system provided by the inventiondepicting the delivery system comprising a housing member provided withmeans for releasably holding an insert member comprising an expandablecomposition for pushing a beneficial agent formulation from the deliverysystem;

FIG. 8 is an opened view of the delivery system of FIG. 3, wherein thedelivery system comprises a first walled member and an engaging secondwalled member, and the opened viewed system also depicts the componentscontained in each walled member;

FIG. 9 is an opened view of the delivery system of FIG. 4 depicting adelivery system comprising a beneficial agent section and a drivingforce section joined as releasable engaging structural member sectionsto provide an integral delivery system;

FIG. 10 is an opened view of a delivery system similar to the deliverysystem of FIG. 9 with the delivery system of FIG. 10 illustrating adifferent array of components contained in the delivery system; and,

FIG. 11 is an opened view of a delivery system provided by the inventionwherein the system embraces another means that closes and is used forforming an exit port in the delivery system.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures areexamples of various delivery systems provided by the invention, andwhich examples are not to be construed as limiting, one example of adelivery system is seen in FIG. 1 as identified by the number 10. InFIG. 1, delivery system 10 comprising a housing 11 formed of a wall 12,which wall surrounds and defines an internal compartment, not seen inFIG. 1. Delivery system 10 comprises at least one exit passageway 13,indicated by a break in wall 12, for delivering a beneficial agentformulation from delivery system 10. In FIG. 1, delivery system 10comprises a dome-shaped rear end 8 and a similar dome-shaped lead end 9for aiding in placing delivery system 10 in an animal host. In anembodiment not seen, delivery system 10 can be manufactured with a pairof flat ends 8 and 9. The expression, "lead end," as used hereingenerally denotes the end from which beneficial agent is released fromthe system.

FIG. 2 depicts another delivery system 10 provided by the invention. InFIG. 2 delivery system 10 comprises housing member 11, which housingmember 11 comprises wall 12 that surrounds and forms an internalcompartment, not seen in FIG. 2. Delivery system 10 comprises lead end 9and rear end 8. In FIG. 2, delivery system 10 comprises break-off orseverable tab 14 at lead end 9. Break-off or severable tab 14 covers anexit passageway, not seen in FIG. 2. Break-off or severable tab 14serves several purposes, it seals delivery system 10 for preventing apremature delivery of a beneficial agent from delivery system 10, ithelps maintain the sterile environment inside delivery system 10, and itprotects the ingredients inside the delivery system from oxidation byair. Break-off tab 14 comprises an optional scored line 15 to enhanceits separation from the delivery system. Break-off or severable tab 14is easily snapped-off at the time of use by manual pressure, by tapping,by twisting, by filing, by cutting, or the like, at the time of use toprovide an exit passageway. The break-off tab 14 can be formed duringmanufacture, it can be jointed to the body member by heat fusion,adhesive joining, or the like.

FIG. 3 depicts another delivery system 10 provided by the invention. InFIG. 3, delivery system 10 comprises body member 11, wall 12, lead end9, rear end 8, tab 14 closing an exit passageway 13. In FIG. 3, deliverysystem 10 comprises a substantially uniform housing 11 throughout itsdimensions. This structure, when delivery system 10 is designed andshaped with substantially uniform longitudinal and circular dimensionsas an implant, provides a means for enhancing its implantable propertiesinto a biological environment comprising muscle tissue, subcutaneousspace or other sensitive implant locations.

FIG. 4 illustrates a delivery system 10 comprising housing member 11,wall 12, exit passageway 13, break-off or severable tab 14, lead end 9and rear end 8. In this application the expression, "lead end,"generally denotes the end the beneficial agent exits the deliverysystem. In use, either end may be implanted first. In FIG. 4, deliverysystem 10 housing 11 comprises a first section 16 and a second section17. The first section 16 and the second section 17 provide (1) an easymethod for manufacturing delivery system 10, (2) a means for selectivelymanufacturing or managing components inside first section 16 differentlyfrom components inside second section 17, which can, for example, permitsterilization of section 16 and components therein by, for example,gaseous sterilization without irradiating the beneficial agent, whichsection 17 can be radiated with sterilizing doses of radiation, (3) ameans for replacing one of sections 16 or 17 during use, and (4) as ameans for enhancing the implant properties of delivery system 10.

FIG. 5 depicts an opened view of delivery system 10 of FIG. 1. Deliverysystem 10 of FIG. 5 comprises a lead end 9, a trailing end 8 and apassageway 13 that connects the exterior with the interior of deliverysystem 10. Delivery system 10 comprises also housing member 11. Housingmember 11 comprises wall 12, which wall 12 comprises a first wallsection 12a and a second wall section 12b. Wall 12, comprising firstwall section 12a and second wall section 12b surrounds and defines aninternal compartment 18. Wall section 12a is the lead end 9, it formspassageway 13 and it surrounds the internal compartment area 18 thatcontains a beneficial agent formulation. Wall section 12a at its enddistant from lead end 9 defines and forms receiving means 19. Receivingmeans 19 is enlarged slightly for receiving second wall section 12b.Wall section 12b surrounds the internal compartment area 18 thatcontains a means for expanding and for occupying space in compartment 18for delivery of a beneficial agent formulation from delivery system 10.The two wall sections, sections 12a and 12b at receiving end 19, areclose in size and they form a tight friction fit therebetween. There isclearance or tolerance in size to allow wall section 12b a slidingmovement into the receiving means 19 of wall section 12a. Wall section12a and wall section 12b can be telescoped completely into a closed, andcontinuous walled position. Optionally, they can be held together byheat fusion, by an adhesive, or the like.

Wall section 12a comprises a composition that is substantiallyimpermeable to the exchange of fluid, beneficial agent and otheringredients contained in delivery system 10. Wall section 12a, in apresently preferred manufacture, is substantially impermeable to theingress of an external fluid to serve as a means for substantiallyprotecting a beneficial agent that is sensitive to fluid from anexterior fluid present in the environment of use. Wall section 12asubstantially restricts and prevents fluid from passing through wall 12aand entering into compartment 18 in the region containing a beneficialagent formulation. Wall section 12b comprises in at least a part asemipermeable wall composition that is permeable to the passage of fluidfor making available fluid to an expandable driving means insidecompartment 18. Wall section 12b is permeable to the passage of fluidand it is substantially impermeable to the passage of other ingredientscontained in delivery system 10. Wall sections 12a and 12b optionallycomprise a plasticizer that imparts flexibility and workability to thewall. Wall 12, comprising sections 12a and 12b, is non-toxic and, in apreferred embodiment, it maintains its physical and chemical integrity,that is, wall 12 does not erode during the dispensing period.

Compartment 18 comprises a beneficial agent formulation, whichbeneficial agent formulation comprises a beneficial agent 20 identifiedby dots, and a pharmaceutically acceptable carrier 21 identified by wavylines. The pharmaceutically acceptable carrier in one presentlypreferred embodiment comprises more than one ingredient, such as abuffer 22 identified by horizontal dashes; a pharmaceutically acceptablevehicle 23 identified by vertical lines; a pharmaceutically acceptablesurfactant 24 identified by slanted lines, and other formulationingredients. Compartment 18 further comprises an expandable drivingmember 25 identified by slanted lines. Expandable driving member 25optionally comprises an osmagent 26, identified by dots, homogeneouslyor heterogeneously blended with expandable driving member 25.Compartment 18 optionally comprises a layer 27, represented byhorizontal lines, which layer 27 is positioned between the beneficialagent formulation and the expandable driving member 25. Layer 27, in apresently preferred embodiment, comprises a composition that issubstantially impermeable to the passage of fluid and it serves torestrict the passage of fluid present in the expandable driving memberinto the beneficial agent formulation; and it operates to essentiallymaintain the integrity of the beneficial agent layer and the drivinglayer. Layer 27 acts also to insure that the expanding driving forcegenerated by the expandable driving member is applied directly againstthe beneficial agent formulation. In operation, as the expandable member25 absorbs and imbibes fluid, it expands and pushes against layer 27causing it to slide inside compartment 18. Layer 27 moves towardspassageway 13, pushing the beneficial agent formulation throughpassageway 13 for maximizing the delivery of the beneficial agent to abiological environment of use, such as livestock.

FIG. 6 is an opened view of FIG. 2 for depicting the structure ofdelivery system 10. Delivery system 10 of FIG. 6 comprises housingmember 11, lead end 9, rear end 8, wall 12, first wall section 12a,second wall section 12b, receiving end 19 of first wall section 12a,internal space 18, beneficial agent 20, pharmaceutically acceptablecarrier 21, nontoxic buffer 22, nontoxic vehicle 23, nontoxic surfactant24, expandable driving member 25, osmotically effective solute 26 andforce transmitting layer 27. In FIG. 6, delivery system 10 comprisesalso break-off tab 14. Break-off or removable tab 14 is broken-off orsevered easily from body member 11 by holding tab 14 between the indexfinger and the thumb of one hand, and by holding body member 11 betweenthe index finger and the thumb of the other hand and snapping theassembly to form an exit passageway. Tab 14 can also be severed bycutting, filing, and the like.

FIG. 7 is an opened view of another embodiment of delivery system 10provided by the invention. In FIG. 7, delivery system 10 compriseshousing member 11, wall 12, lead end 9, rear end 8, break-off tab 14,internal compartment 18 that contains beneficial agent 20,pharmaceutically acceptable carrier 21, nontoxic buffer 22, nontoxicagent vehicle 23 which vehicle 23 also functions as a viscosityenhancer, and a nontoxic surfactant 24. In FIG. 7, wall 12 is continuousand it extends the length of delivery system 10. Wall 12, at its end 8distant from lead end 9, comprises a receiving end 19. Receiving end 19is designed and adapted for receiving insert 28. Insert 28 is cup-likein shape, or tube-like with a single closed end, and it is made of acomposition such a polymeric composition that is permeable to thepassage of an external fluid. Insert 28 comprises an expandable volumeconsuming member 25 comprising an optional osmotically effective solute26, and a layer or partition 27 that separates expandable member 25 fromthe other ingredients present in compartment 18. Insert 28 in end 19, ina presently preferred embodiment, is replaceable and one or more thanone insert 28 can be used during the operation of delivery system 10.

FIG. 8 is an opened view of the delivery system 10 illustrated inaccompanying FIG. 3. In FIG. 8, delivery system 10 comprises housingmember 11 formed by wall 12. Wall 12 comprises (1) a first section 12athat surrounds an internal compartment area containing a beneficialagent, and (2) a second section 12b that surrounds an internalcompartment area comprising at least one means for occupying space inthe compartment. First wall section 12a is provided with receiving means19. Wall 12a at receiving means 19 is thinner and it exhibits a smallerinternal dimensions for receiving second section 12b at its opened end7. Wall section 12b is thinner at its opened end 7 and it exhibits asmaller external dimensions for sliding into receiving end 19 in matedrelation for providing an essentially continuous wall 12. The twosections can be joined together by various techniques such as solventweld, adhesive bond, thermal weld, ultrasonic weld, spin weld, inductionweld, or by similar welding or bonding operations. First wall section12a and second wall section 12b in the delivery system 10 seen in FIG. 8are substantially uniform in cross-sectional dimensions therebyproviding delivery system 10 with substantially uniform dimensions alongits central axis. Delivery system 10 in FIG. 8 also comprises lead end9, rear end 8, break-off tab 14, internal compartment 18, beneficialagent 20, pharmaceutically acceptable carrier 21, pharmaceuticallyacceptable vehicle 23, and a pharmaceutically acceptable solvent 24. Ina presently preferred embodiment delivery system 10 comprises amultiplicity of expandable driving member 25a, 25b and 25c. Expandabledriving members 25a, 25b and 25c comprise like or unlike compositions.For example, members 25a, 25b and 25c can be made as tablets comprisinglike osmopolymers or like osmagents, or they can comprise unlikeosmopolymers or unlike osmagents. The osmopolymers and the osmagents canbe made as tablets and inserted through open end 7 successively intosecond wall member 12b. Also, member 25a, 25b and 25c can be different.For example, member 25a comprises an osmopolymer, member 25b comprisesan osmagent, and member 25c comprises an osmopolymer, or member 25acomprises an osmagent, member 25a comprises an osmopolymer, and member25c comprises an osmagent, and the like. Delivery system 10 in apresently preferred manufacture comprises layer 27 that separates thebeneficial agent formulation from the expandable driving members.

FIG. 9 is an opened view of the delivery system 10 illustrated in FIG.4. In FIG. 9, delivery system 10 comprises housing member 11, wall 12comprising first section 12a, second section 12b, lead end 9, rear end8, break-off tab 14, receiving means 19, opening 7 in wall member 12b,beneficial agent 20, pharmaceutically acceptable carrier 21,pharmaceutically acceptable buffer 22, pharmaceutically acceptableviscosity enhancing vehicle 23, and a pharmaceutically acceptablesurfactant 24. In FIG. 9, the first section 12a functions as a firstbody portion 12a of delivery system 10, and it is designed for slippingover, or for receiving second section 12b that serves as a second bodyportion 12b. The second body portion is telescopically capped by theengaging first body portion 12a. In FIG. 9, delivery system 10 comprisesa partition 27 positioned near the filling end of first section 12a, andat the filling entrance of second section 12b comprises a plurality ofdriving members 25a, 25b, 25c, 25d and 25e. The members are presentlyformed as depots or layers of the same or different member formingcomposition selected from the group consisting of an osmopolymer, anosmagent, or a composition comprising an osmopolymer and an osmagent.

FIG. 10 is an opened view of FIG. 4 taken in conjunction with FIG. 6 forillustrating the structure of delivery system 10. In FIG. 10, deliverysystem 10 comprises housing member 11, wall 12 comprising first section12a, second section 12b, lead end 9, rear end 8, break-off tab 14,receiving end 19, opening 7, beneficial agent 20, pharmaceuticallyacceptable carrier 21, pharmaceutically acceptable buffer 22,pharmaceutically acceptable viscosity modulating vehicle 23,pharmaceutically acceptable surfactant 24, non-toxic partition 27, anddriving members 25a, 25b and 25c selected from the group consisting ofan osmopolymer, an osmagent, and an osmopolymer containing an osmagent.In FIG. 10, one example of delivery system 10 is manufactured as animplant comprising a body length of about 50.12 mm, a diameter of about4.97 mm, the beneficial agent formulation occupying a length of 33.27mm, a partition occupying a space of 5.08 mm, and an initial total spaceof 7.62 mm occupied by the expandable members. The optional break-offtab is about 6.07 mm in length and when broken off it forms an exitpassageway of 0.64 mm. The implant can be implanted into receivingtissue using an implanter. Generally, an implanter comprises a tubularmember with a central longitudinal axial bore, a pointed, elongated,annular concavely beveled implanting end and an implant charging end.The implanting end and the charging end communicate through a bore. Aplunger adapted to be removably inserted in the bore is designed forslidable movement therein for applying the necessary force forimplanting the implant. Also, the implant can be surgically implanted inthe muscle or other tissue of livestock.

In drawing FIG. 11, a dosage form 10 is seen in opened section, whichdosage delivery form 10 is similar in structure and in operation todelivery form 10 illustrated in drawing FIG. 10. In drawing FIG. 11,dosage form 10 comprises a shortened tab 14. The shortened tab 14 issheared, cut-off, severed, pryed-off, bent or broken-off in an implantinjection device. The shortened tab 14 also can be snapped-off bypushing tab 14 against a sterile surface, prior to implanting it inlivestock. In FIG. 11, system 10 also comprises a tapered end 8.

The delivery systems 10 of FIGS. 1 through 11 can be manufactured fordelivering numerous beneficial agents, including drugs at a controlledrate, to a presently preferred biological environment of use such aswarm-blooded animals including humans, ruminants, hog, swine, porcineand the like. The delivery system provides for high loading of abeneficial agent and for its delivery in beneficially effective amountsover time. It is to be understood the delivery systems are not to beconstrued as limiting, as the delivery systems can take a wide varietyof shapes, sizes and forms adapted for delivering beneficial agents toenvironments of use. For example, the delivery systems manufactured asdelivery devices can be used for dispensing a beneficial agent in theanal-rectal passageway, in the cervical canal, as an artificial gland,in the vagina, as a subcutaneous implant, and the like. The deliverysystem can be used in hospitals, nursing homes, outpatient clinics,veterinary clinics, sickrooms, farms, zoos and other environments ofuse.

DETAILED DESCRIPTIONS OF THE INVENTION

In accordance with the practice of this invention, it has now been foundthat delivery system 10 can be manufactured with a first wall section12a that surrounds the compartment's internal space initially occupiedby the beneficial agent formulation. First wall section 12a comprises acomposition that does not adversely effect the beneficial agent, theosmopolymer, the osmagent, other ingredients in delivery system 10, thehost, or the like. First wall section 12a comprises a composition thatis a means that substantially limits or prevents the passage of anexternal fluid into delivery system 10. The phrase, "substantiallylimits or prevents," as used herein, indicates the volume of externalfluid passing through first section wall 12a is substantiallynegligible, that is, about zero up to about 1μ or up to about 1 ml perday. Typical compositions for forming first section 12a are vinylidenechloride copolymers and terpolymers such as vinylidene chloride-vinylchloride copolymer, vinylidene chloride-acrylonitrile copolymer,vinylidene chloride-styrene copolymer, and vinylidene chloride-vinylchloride-acrylonitrile terpolymer; acrylonitrile polymers such asacrylonitrile-methyl vinyl ether copolmer, acrylonitrile-styrenecopolymer, acrylonitrile-butadiene-styrene terpolymer, and the like;halogenated polymers such as chlorinated polyether,polytetrafluroethylene, polychlorotrifluoroethylene, copolymertetrafluroethylene and hexafluropropylene, polyvinylfluoride,polyvinyl-chlorobuteral, plasticized polyvinylidene chloride, and thelike; nylon; polyamide-imide; polyarylether; polysulfone; polycarbonate;high density polyethylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; glass; bakelite;melamine; polystyrene; stainless steel, and the like. The water vaportransmission rate through compositions useful for forming first wall 12aare reported in J. Pharm. Sci., Vol. 59, pp 1634-37, (1970); in Ind.Eng., Chem., Vol. 45, pp 2296-2306, (1953); Materials Engineering, Vol.5, pp 38-45, (1972); in Ann. Book of ASTM Stds., Vol. 08.02, pp 208-11and pp 584-87, (1984); and in Ind. and Engin. Chem., Vol. 49, pp1933-36, (1957). The polymers are known in the Handbook of CommonPolymers, by Scott and Roff, CRC Press, Cleveland Rubber Co., Cleveland,Ohio.

The second wall section 12b comprises a composition comprising meansthat aids in controlling fluid flux into the compartment area occupiedby the expandable driving member. The composition is permeable to thepassage of external fluids such as water and biological fluids, and itis substantially impermeable to the passage of beneficial agents,osmopolymers, osmagents, and the like. Typical compositions comprisesemipermeable materials for forming wall 12b are, in one presentlypreferred embodiment, a member selected from the group consisting of acellulose ester, a cellulose ether and a cellulose ester-ether. Thesecellulosic polymers have a degree of substitution, D.S., on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By, "degreeof substitution," or "D.S.," is meant the average number of hydroxylgroups originally present on the anhydroglucose unit comprising thecellulose polymer that are replaced by a substituting group.Representative materials include, but are not limited to, a memberselected from the group consisting of cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, mono-, di-, and tricellulose alkanylates, mono-,di-, and tricellulose aroylates, and the like. Exemplary cellulosicpolymers include cellulose acetate having a D.S. up to 1 and an acetylcontent up to 21%; cellulose acetate having a D.S. of 1 to 2 and anacetyl content of 21% to 35%; cellulose acetate having a D.S. of 2 to 3and an acetyl content of 35% to 44.8%, and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propionyl content of 39.2% to 45% and a hydroxyl content of 2.8%to 5.4%; cellulose acetate butyrate having a D.S. of 1.8 and an acetylcontent of 13% to 15% and a butyryl content of 34% to 39%; celluloseacetate butyrate having an acetyl content of 2% to 29%, a butyrylcontent of 17% to 53% and a hydroxyl content of 0.5% to 4.7%; celluloseacetate butyrate having a D.S. of 1.8, and acetyl content of 4% averageweight percent and a butyryl content of 51%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentate; coesters of cellulose such ascellulose acetate butyrate and cellulose, cellulose acetate propionate,and the like. The amount of semipermeable materials presently preferredin wall 12b is about 20% to 100%.

Representative materials that can be used to regulate further the fluidflux of wall 12b include materials that decrease the fluid flux andmaterials that increase the fluid flux of wall 12b. Materials optionallyadded to wall 12b for decreasing the flux comprise a member selectedfrom the group consisting of polyacrylate; polymethacrylate;polysulfone; polyacrylic ester; polyacrylonitrile; polyacrylamide;polystyrene; polycaprolactam; polyhexamethylene adipamide;polyhexamethylene sebacamide; polyepoxide; polyformaldehyde, and thelike. Materials that increase the permeability of wall section 12b tothe passage of an exterior fluid include polyvinyl alcohol;poly(1,4-anhydro-beta-D-mannuroni acid); polyester derived from thecondensation of a polyhydric alcohol and a polyfunctional acid whereinthe functionality refers to reactive groups such as hydroxyl, carboxyl,and the like; polysaccharides; hydroxy alkylcellulose having a molecularweight of 9,000 to 35,000; polyalkylene glycol, and the like. Theconcentration of means for regulating the flux in wall 12b is about 5%to 50%.

The fluid flux through wall 12 comprising a polymeric composition can bemeasured by techniques known to the art. One technique that has beenfound to be eminently well-suited is to cast or hot press a film of thecomposition to a thickness in the range of 1 to 60 mils. The film isused as a barrier between a fluid source and a container initially freeof fluid. Then, by measuring the volume of fluid that passed through afilm of known area and thickness, the flux is easily ascertained bystandard techniques known to the art as recorded in J. Pharm. Sci., Vol.52, pp 1145-49, (1963); ibid., Vol. 53, pp 798-802, (1964); ibid., Vol.54, pp 1459-64, (1965); ibid., Vol. 55, pp 840-43 and pp 1224-39,(1966); Encyl. Polymer. Sci. Technol., Vol. 5 and 9, pp 65-82, and pp794-807, (1968), and references cited therein; in U.S. Pat. Nos.3,854,480; 3,845,761 and 3,896,819. Second wall 12b section that exhibita fluid permeability of 10⁻⁶ to 10⁻¹ (cc.mil/cm².hr atm) can be used forthe purpose of this invention. The polymers are known to the art in theHandbook of Common Polymers, by J. R. Scott and W. J. Roff, (1971),published by CRC Press, Cleveland, Ohio.

First wall section 12a and second wall section 12b optionally comprise anon-toxic plasticizer. Representative plasticizers suitable for formingwall 12a and wall 12b include plasticizers that lower the temperature ofthe second-order phase of transition of wall 12a and wall 12b, or theelastic modules of wall 12a and wall 12b; also the plasticizers increasethe workability of wall 12a and wall 12b and their flexibility.Plasticizers operable for the present purpose include straight chain andbranched chain plasticizers, cyclic plasticizers, acrylic plasticizersand heterolcyclic plasticizers. Representative plasticizers include amember selected from the group consistent of phthalate, phosphate,citrate, adipate, tartrate, sebacate, succinate, glycolate, glycerolate,benzoate, myristate, sulfonamide and halogenated plasticizer. Generallywall 12a or wall 12b will comprise from 1% to 45% plasticizers or more,with the total concentration of all ingredients in a wall equal to 100%.

Representative plasticizers include dialkyl phthalate, dicycloalkylphthalate, diaryl phthalate, dimethyl phthalate, dipropyl phthalate,di(2-ethylhexyl) phthalate, di-isopropyl phthalate, alkyl phosphate,aryl phosphate, tributyl phosphate, trioctyl phosphate, tricresylphosphate and triphenyl phosphate; alkyl citrate, citrate esters,tributyl citrate, triethyl citrate and acetyl triethyl citrate; alkyladipates such as dioctyl adipate, diethyl adipate anddi(2-methoxyethyl)-adipate; dialkyl tartrates such as diethyl tartrate,and butyl tartrate; alkyl sebacates such as diethyl sebacate, dipropylsebacate and dinonyl sebacate; alkyl succinates such as diethylsuccinate and dimethyl succinate; alkylglycolates, alkyl glycerolates,glycol esters and glycerol esters such as glycerol diacetate, glyceroltriacetate, glycerol monolactate diacetate, methyl phythayl ethylglycolate, and the like.

Suitable plasticizers can be selected for blending with the wall 12a orwall 12b forming materials by selecting plasticizers that have a highdegree of solvent power for the materials, are compatible with thematerials over both the processing and use temperature range, exhibitpermanence as seen by its strong tendency to remain in the plasticizedwall, both in storage and in the biological environment of use, impartsflexibility to the material, and are non-toxic to animals, humans,avians, fishes and reptiles. Procedures for selecting a plasticizerhaving the described characteristics are disclosed in the Encyclopediaof Polymer Sciences and Technology, Vol. 10, pp 118-306, (1969),published by John Wiley & Sons, Inc. Also, a detailed descriptionpertaining to the measurement of plasticizer properties includingsolvent parameters and compatibility, such as the Hildebrand solubilityparameter δ, the Flory-Huggins interaction parameter μ, and theFlory-Huggins interaction parameter μ, and the cohesive-energy density,CED, parameters are disclosed in "Plasticization and PlasticizerProcesses," Advances in Chemistry, Series 48, Chapt. 1, pp 1-26, (1965),published by the American Chemical Society, and in U.S. Pat. No.4,077,407.

Delivery system 10 in its compartment 18 comprises a beneficial agent 20that produces a desired and useful result when administered to awarm-blooded animal including humans and farm animals. The beneficialagent 20 is useful in one embodiment for increasing the rate of growthand the efficiency of feed utilization in equine, bovine and swine. Thebeneficial agent 20 in another embodiment is useful for controllingestrus and ovulation in the course of breeding farm animals forcommercial purposes, for effecting contraception and for producing ananabolic response associated with the inhibition of estrus. Beneficialagent 20 in another embodiment is a drug useful for producing atherapeutic effect. The beneficial agent 20 that can be administered bydelivery device 10, as provided by the invention, comprises beneficialagents 20 that act at synaptic and neuroeffector sites, beneficialagents acting on the central nervous system, autocoids,anti-inflammatory, analgesic, antipyretic, cardiovascular, and the like.

Representative beneficial agent 20 that can be administered by deliverysystem 10 include pharmacologically active peptides and proteins,anabolic hormones, growth promoting hormones, hormones related to theendocrine system comprising porcine growth promoting hormone, bovinegrowth promoting hormone, equine growth promoting hormone, ovine growthpromoting hormone, human growth promoting hormone, growth promotinghormones derived by extraction and concentration from pituitary andhypothalmus glands, growth promoting hormones produced by recombinantDNA methods, bovine growth promoting hormone as described in NucleicAcid Res., Vol. 10, p 7197 (1982), ovine growth promoting hormone asdescribed in Arch. Biochem. Biophys., Vol. 156, p 493 (1973), andporcine growth promoting hormone as described in DNA, Vol. 2, pp 37, 45,(1983). The polypeptides also comprise growth hormone, somatropin,somatotropin, somatotropin analogues, modified porcine somatotropin,modified bovine somatotropin, derivatives of both porcine and bovinesomatotropin, somatomedin-C, gonadotropic releasing hormone, folliclestimulating hormone, luteinizing hormone, LH-RH, growth hormonereleasing factor, gonadotropin releasing factor, insulin, colchicine,chorionic gonadotropin, oxytocin, somatotropin plus an amino acid,vasopressin, adrenocorticotrophic hormone, epidermal growth factor,prolactin, somatostatin, somatotropin plus a protein, cosyntropin,lypressin, polypeptides such as thyrotropin releasing hormone, thyroidstimulating hormone, secretin, pancreozymin, enkephalin, glucagon,endocrine agents secreted internally and distributed in an animal by wayof the bloodstream, and the like. The beneficial agents and their dosageunit amounts are known to the prior art in The Pharmacological Basis ofTherapeutics, by Gilman, Goodman, Rall and Murad, 7th Ed., (1985)published by MacMillan Publishing Co., N.Y.; in Pharmaceutical Sciences,Remington, 17th Ed., (1985) published by Mack Publishing Co., Easton,Pa., and in U.S. Pat. No. 4,526,938. Generally, the delivery system 10comprises from about 5 nanograms to 20 grams of beneficial agent 20.

Pharmaceutical carrier 21, in compartment 18, comprise beneficial agent20, pharmaceutically acceptable viscosity modulating vehicle 23, abuffer 22, or a buffer solution 22 and a surfactant 24. Thepharmaceutically acceptable viscosity modulating means 23 in a presentlypreferred embodiment comprises a polyol such as a diol, triol,polyhydric alcohol, and the like. More specific polyols comprise1,5-pentylene glycol; 1,6-hexylene glycol; 1,7-heptylene glycol;1,9-nonylene glycol; 1,2-dimethyl-1,6-hexylene glycol;1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol;1,2,4-butanetriol; dipentaerythriol, and the like. In another embodimentthe pharmaceutically acceptable vehicle 23 comprises glycerol mono(loweralkyl) ethers and glycerol di(lower alkyl) ethers such as glycerol1-methyl ether; glycerol 1-ethyl ether; glycerol 1,2-dimethyl ether;glycerol 1,3-dimethyl ether, and the like. In another embodiment thepharmaceutically acceptable vehicle 23 comprises a mixture such aspropylene glycol and glycerol; a mixture comprising propylene glycol,ethanol and glycerol, and the like. The pharmaceutically acceptablevehicle 23 functions as a viscosity modulating means for the componentspresent in a compartment 18, as a vehicle for transporting beneficialagent 18 from compartment 20, it provides protection against thedecomposition of a beneficial agent, and it imparts physical chemicalstability to components present in compartment 18. The viscositymodulating vehicle may be used to increase the viscosity of theformulation to prevent mixing fluids in the implantation environmentfrom mixing with the beneficial agent carried in formulation withincompartment 18. The pharmaceutically acceptable modulating means 23 ispresent in the compartment 18 is about 0.1% to 90%.

Representative pharmaceutically acceptable buffers 22, in compartment18, that are blended with the beneficial agent 20 and thepharmaceutically acceptable fluid 23 comprise nontoxic buffer andsolution thereof, solutions that resist change of pH thereby givingstability to the components present in compartment 18. In anotherembodiment the buffer and solutions thereof can be used alone and, in apresently preferred embodiment, the buffer and solution thereof is usedin combination with the pharmaceutically and pharmacologicallyacceptable aqueous miscible fluids. Typical buffer aqueous solutionscomprise sodium dihydrogen phosphate (0.025M) and disodium monohydrogenphosphate (0.025M); sodium dihydrogen phosphate (0.025M), disodiummonohydrogen phosphate (0.025M) and sodium chloride (0.15M); sodiumcarbonate (0.025M), sodium monohydrogen carbonate (0.025M) and sodiumchloride (0.15M); potassium dihydrogen phosphate (0.025M) and sodiummonohydrogen phosphate (0.025M); potassium dihydrogen phosphate(0.0087M) and sodium monohydrogen phosphate (0.0302M); potassiumhydrogen tartrate (0.034M) and potassium dihydrogen phosphate (0.025M);acetic acid (0.1M) and sodium acetate (0.1M), and the like. The bufferscomprise also citric acid and sodium hydroxide; potassium hydrogenphthatate and sodium hydroxide; potassium hydrogen phosphate and sodiumphosphate; tris(hydroxymethyl) aminomethane and hydrochloric acid;sodium tetraborate and hydrochloric acid; glycine and hydrochloric acid;triethanolamine and hydrochloric acid; N-tris(hydroxymethyl)methyl-2-amino sulfonic acid and sodium hydroxide, andthe like. The buffer aqueous solution in another embodiment can comprisea sole component such as sodium phosphate monobasic, sodium phosphatedibasic, potassium hydrogen tartrate, potassium dihydrogen citrate,potassium hydrogen phthalate, sodium tetraborate, sodium carbonate,sodium hydrogen carbonate and the like.

Representative pharmaceutically acceptable surfactants 24 for thepresent purpose comprise anionic, cationic, amphoteric and nonionicsurfactants. More specific examples of surfactants comprise sorbitantrioleate, sorbitan tristearate, propylene glycol monostearate; sorbitansesquiolate; glycerol monostearate; sorbitan monooleate; propyleneglycol monolaurate; sorbitan monostearate; diethylene glycolmonostearate; glycerol monostearate; diethylmonolaurate; sorbitanmonopalmitate; sorbitan monolaurate; polyoxyethylene lauryl ether;polyoxyethylene sorbitan monostearate; polyoxyethylene sorbitanmonooleate; polyoxyethylene sorbitan tristearate; polyoxyethylenesorbitan trioleate; polyoxyethylene glycol monooleate; polyoxyethyleneglycol monostearate; triethanolamine oleate; polyoxyethylene monylphenol; polyethylene glycol monolaurate; polyoxyethylene sorbitanmonolaurate; polyoxyethylene sorbitan monostearate; polyoxyethylenesorbitan monooleate; polyoxyethylene stearyl ether; polyoxyethyleneoleyl ether; polyoxyethylene sorbitan monopalmitate; polyoxyethylenecetyl ether; polyoxyethylene stearate; sodium oleate; potassium oleate;cetyl ethyl morpholinium ethosulfate; sodium lauryl sulfate; sodiumcaprylate; sodium caprate; sodium laurate; sodium myristate; sodiumcholate; sodium desoxycholate; sodium dihydrocholate;tetradecyltrimethyl ammonium bromide; hexadecylpyridinium chloride;Tween 20; Tween 30; Tween 80, and the like. The amount of surfactantused for producing a pharmaceutically acceptable carrier comprising thebeneficial agent, the buffer, the pharmaceutically acceptable fluid, isabout 0.001% to 7.5%. Generally, the compartment 18 compositioncomprises from 0.5% to 50% beneficial agent, from 20% to 45% aqueousbuffer, from 10% to 75% pharmaceutical viscosity modifying means, andfrom 0.001% to 7.5% surfactant, with the total of all components 100%;and in a more preferred embodiment the composition comprises 25% to 35%beneficial agent, 25% to 35% aqueous buffer solution, 25% to 50%pharmaceutically acceptable viscosity modifying vehicle, and 0.01% to 1%surfactant, with the total of all components 100%. The pharmaceuticallyacceptable fluid carrier members and the surfactants are known inPharmaceutical Science, by Remington, 14 Ed., (1970), published by MackPublishing Co., Easton, Pa., and the buffers are known in Lange'sHandbook of Chemists, 13th Ed., (1985), published by McGraw-Hill Co.,New York, N.Y.

The expandable driving means 25 operable for pushing the beneficialagent composition 20 from delivery system 10, comprises, in a presentlypreferred embodiment, a swellable hydrophilic polymer. Hydrophilicpolymers are known also as osmopolymers. The osmopolymers interact withwater and aqueous biological fluids and swell or expand to anequilibrium state. The osmopolymers exhibit the ability to swell inwater and to retain a significant portion of the imbibed and absorbedwater within the polymer structure. The osmopolymers swell or expand toa very high degree, usually exhibiting a 2 to 50 fold volume increase.The osmopolymers can be noncross-linked or cross-linked. The swellable,hydrophilic polymers are, in one presently preferred embodiment, lightlycross-linked, such as cross-links being formed by covalent or ionicbonds. The osmopolymers can be of plant, animal or synthetic origin.Hydrophilic polymers suitable for the present purpose includepoly(hydroxyalkylmethacrylate) having a molecular weight of from 30,000to 5,000,000; poly(vinylpyrrolidone) having molecular weight of from10,000 to 360,000; anionic and cationic hydrogels; polyelectrolytecomplexes; poly(vinyl alcohol) having a low acetate residual,cross-linked with glyoxal, formaldehyde, or glutaraldehyde and having adegree of polymerization from 200 to 30,000; a mixture of methylcellulose, cross-linked agar and carboxymethyl cellulose; a waterinsoluble, water swellable copolymer produced by forming a dispersion offinely divided copolymer of maleic anhydride with styrene, ethylene,propylene, butylene or isobutylene cross-linked with from 0.0001 toabout 0.5 moles of polyunsaturated cross-linking agent per mole ofmaleic anhydride in the copolymer; water swellable polymers of N-vinyllactams, and the like.

Other osmopolymers operable as the expandable driving member 25 andinitially surrounded by second wall section 12b comprise polymers thatform hydrogels such as Carbopol® acidic carboxy polymers generallyhaving a molecular weight of 450,000 to 4,000,000; the sodium salt ofCarbopol® acidic carboxy polymers and other metal salts; Cyanamer®polyacrylamides; cross-linked water swellable indine-maleic anhydridepolymers; Goodrite® polyacrylic acid having, but not limited to, amolecular weight of 80,000 to 200,000, and the sodium and other metalsalts; Polyox® polyethylene oxide polymers having a molecular weight of100,000 to 5,000,000; starch graft copolymers; AquaKeeps® acrylatepolymers; diester cross-linked polyglucan, and the like. Representativepolymers that form hydrogels are known to the prior art in U.S. Pat. No.3,865,108 issued to Hartop; U.S. Pat. No. 4,002,173 issued to Manning;U.S. Pat. No. 4,207,893 issued to Michaels, and in Handbook of CommonPolymers, by Scott and Roff, published by the Chemical Rubber Company,CRC Press, Cleveland, Ohio.

The expandable driving member 25 in another preferred embodimentcomprises an optional osmagent 26 dispersed therein. The osmagents areknown also as osmotically effective solutes and they are also known asosmotically effective compounds. The osmotically effective compoundsthat can be used for the purpose of this invention include inorganic andorganic compounds that exhibit an osmotic pressure gradient across asemipermeable wall. The osmotically effective compounds, along with theosmopolymers, imbibe fluid into the device thereby making available insitu fluid for imbibition by an osmopolymer to enhance its expansion.The osmotically effective compounds are used by mixing them with theosmopolymer, homogeneously or heterogeneously and then charging theminto the delivery system. Osmotically effective solutes used for theformer purpose include magnesium sulfate, magnesium chloride, sodiumchloride, potassium chloride, potassium sulfate, sodium sulfate, lithiumsulfate, potassium acid phosphate, d-mannitol, urea, inositol, magnesiumsuccinate, tartaric acid, carbohydrates such as raffinos, sucrose,glucose, α-d-lactose monohydrate, mannitol, and mixtures thereof. Theamount of osmagent in the blend with the osmopolymer usually is from 1%to 40%, or higher, with the total of all ingredients comprising thesecond composition equal to 100%.

The expandable driving member 25 in another preferred embodimentcomprises an osmagent. The osmagent 26 can comprise a tablet, a layer,or osmagent 26 can be pressed into second wall section 12b. The osmagentcan be in any suitable form such as particles, crystals, pellets,granules, and the like, when pressed into a tablet layer and into wallsection 12b. Various osmotically effective solutes comprising magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate,potassium chloride, calcium carbonate, potassium acid phosphate, sodiumlactate, calcium lactate, mannitol, urea, inositol, magnesium succinate,tartaric acid, soluble carbohydrates such as raffinose, sucrose,glucose, lactose, mixtures thereof, and the like, can be used for thisembodiment. The osmotic pressure of an osmagent, or an osmopolymer, canbe measured using an osmometer. An osmometer used for the presentmeasurements is identified as Model 320B, Vapor Pressure Osmometer,manufactured by the Hewlett Packard Co., Avondale, Pa. Osmagents andosmopolymers are known to the art in U.S. Pat. Nos. 4,327,725 and4,612,008.

Layer 27, positioned between the beneficial agent composition and theexpandable driving member is a means for (1) maintaining the separateidentity of the beneficial agent composition and the driving member, for(2) transmitting the force generated by the driving member against thebeneficial agent composition, and (3) for substantially restricting thepassage of fluid between the beneficial agent composition and thedriving member. Layer 27 comprises in one embodiment, an olefin, avinyl, a condensation, an addition, an organosilicon, or an inorganicpolymer. More specific polymer composition comprise high densitypolyethylene, high density polypropylene, polystyrene, polycarbonate,polyamide, elastomers, chlorinated rubber, styrene-butadiene rubber,chloroprene rubber, silicone, glass, and the like. In a presentlypreferred embodiment, layer 27 comprises a wax. More preferably, thewaxes exhibit a melting point or a solidification point of about 45° C.or higher, usually 45° C. to 110° C. The waxes are selected frommineral, vegetable, plant, fish, animal, petroleum, and synthetic waxes.Representative waxes comprise a member selected from the groupconsisting of montan wax, ozokerite wax, carnuba wax, myricyl cerotatewax, beeswax, spermaceti wax, ceresini wax, gama wax, Japan wax,ouricury wax, ceresin wax, castor wax, Witco wax, polyethylene wax, andthe like. Additionally, reinforcing agents such as Cabosil® material canbe incorporated into the wax for improving its structural integrity. Inanother manufacture, layer 27 can comprise a polymer elastomerpossessing properties of low Shore A hardness, and Young's modulus,thermoplastic or thermoset, and essentially water impermeable.

The phrase, "exit means 13," as used herein, comprises means and methodssuitable for the metered release of the beneficial agent 20 fromcompartment 18 of delivery system 10. The exit means 13 includes atleast one passageway, orifice, or the like, through wall 12 forcommunicating with compartment 18. The expression, "at least onepassageway," includes aperture, orifice, bore, pore, porous elementthrough which the agent can migrate, hollow fiber, capillary tube,porous overlay, porous insert, and the like. The expression alsoincludes material that erodes or is leached from the wall in the fluidenvironment of use to produce at least one passageway in dosage form 10.Representative material suitable for forming at least one passageway, ora multiplicity of passageways, include an erodible poly(glycolic) acidor poly(lactic) acid member in the wall; a gelatinous filament;poly(vinyl alcohol); leachable materials such as fluid removable poreforming polysaccharides, salts, or oxides, and the like. The expressionincludes structural characteristics that concentrate stress at a precisepoint in the wall so that only a small amount of force will inducebreakage in the wall, yielding a passageway through the wall fromcompartment 18 to the outside of the device. A passageway or a pluralityof passageways can be formed by leaching a material such as sorbitol,lactose and like water-soluble solids from the wall. The passageway canhave any shape such as round, triangular, square, elliptical, and thelike, for assisting in the metered release of beneficial agent fromdosage form 10. Dosage form 10 can be constructed with one or morepassageways in spaced apart relations or more than a single surface of adosage form. Passageways and equipment for forming passageways aredisclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and4,008,864. Passageways formed by leaching are disclosed in U.S. Pat.Nos. 4,200,098 and 4,285,987.

Delivery system 10 can be manufactured by standard manufacturingtechniques. In one process, the first wall section 12a, and the secondwall section 12b, independently are injection molded or extruded intothe desired shape. Then, the first wall section 12a is filled with thebeneficial agent composition comprising the beneficial agent, thepharmaceutically acceptable carrier, the pharmaceutically acceptablebuffer and other components. Then, the second wall section 12b is filledwith an expandable driving member and the layered partition next addedthereto in layered arrangement. Optionally, the partition may be addedto the first wall section 12a after filling with beneficial agent, inaddition to, or instead of the partition added to second wall section12b. Next, the two sections at their ends are slid together and they areoptionally heat sealed, adhesive sealed, or solvent sealed, orultrasonically sealed, or radiofrequency sealed, or spin welded, alsoknown as friction heating to weld. Then, at least one passageway isdrilled in the lead end of the manufactured assembly. Optionally, apassageway is drilled, or preformed in the wall and sealed with abreak-off tab that is broken open, or cut open, or the like at the timeof use to connect through the passageway the beneficial agentcomposition with the exterior of delivery system 10.

DETAILED DESCRIPTION OF EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

A delivery system manufactured in the shape of an implantable deliverydevice comprising a lead end with an exit passageway and a distant rearend is manufactured as follows: first, an expandable driving member isprepared by adding 9.5 liters of water and 500 g of polyvinylpyrrolidone to a stainless steel container and the components mixed for20 hours to obtain a smooth, binder solution. Next, 34.6 kg of sodiumCarbomer®, a sodium salt of polyacrylic acid polymer, is sized byforcing it through a 0.028 inch mesh screen in a fluid air mill set at780-800 rpm speed. Then, 33 kg of the screened polymer is transferred tothe granulator bowl of a fluid bed granulator and 6.6 liters of thebinder solution is slowly sprayed onto the polymers in the granulator.The polymer granules are formed in this manner.

Next, 15 kg of sodium chloride is milled in a mill to a number 21 sizemesh screen. Then, 31.32 kg of the granules of sodium Carbomerosmopolymer is mixed with 13.68 kg of the milled sodium chloride and themix blended for about one hour. Then 455 gm of magnesium stearate isadded and the ingredients blended for 10 minutes to produce ahomogeneous expandable driving composition. The composition next ispressed into osmotically active tablets in a table press at a pressureof 500 lbs to produce a round, flat faced 30 mg tablet.

The semipermeable wall that surrounds a compartment for containing theosmotically active tablet is prepared as follows: first, 3.85 kg ofcellulose acetate butyrate and 1.15 kg of tributyl citrate are dry mixedin a mixer for 5 minutes. This produced a polymer plasticizer blend of a77/23 ratio for the rate controlling wall 12b. Next, a rubber mill isused to melt blend the blend, at a roller temperature of 70° C. Theblend is transferred to the moving rollers of the mill and mixed for 3minutes. Then, after all the materials are added to the mill, thetemperature is raised to 90° C., followed by milling for 2 minutes, nextthe temperature is raised to 115° C. and followed by two more millingminutes, then the temperature is increased to 133° C. and followed bysix minutes of milling the blend, and then the temperature is increasedto 144° C. and followed by six minutes of milling the blend. After therollers are cooled to 50° C., the blend is removed from the mill. Themilled blend is cut into strips and passed through a grinder mill, andthe resulting particles fed into an injection molder and molded into thesemipermeable wall surrounding a compartment with an opened end forreceiving an expandable driving member and for mating with the leadsection of the delivery system.

Next, the lead, first wall section of the delivery system is prepared byadding 5 kg of polycarbonate to a hopper dryer and drying the polymer at250° F. for 4 hours. Then, the dry polymer is fed into the hopper of aninjection molder, where a single cavity hot tip mold is used toinjection mold an impermeable wall surrounding a compartment with anopen end for receiving components and for mating with the semipermeablewall member.

Next, the delivery system is assembled by first charging the subassemblysemipermeable walled member with three osmotic tablets. Then,microcrystalline wax is melted and the molten wax poured on the top ofthe osmotic tablet to completely fill to the opened walled member. Thecharged subassembly is allowed to cool to room temperature.

Next, the delivery system subassembly comprising the substantiallyimpermeable wall surrounding the compartment is filled with 340 mg offormulation at 40° C., wherein the formulation comprises 33 wt % (weightpercent) porcine somatotropin, 4.57 wt % sodium phosphate monobasic,28.1 wt % water, 33.3 wt % glycerol, and 0.67 wt % Tween-80. Then, thetwo subassemblies at their opened ends are joined by inserting partiallythe member comprising the osmotic tablets and the wax into the membercomprising the formulation. Next, 4 drops of moisture-cured cyanoacrylicadhesive are dropped onto the remaining exposed surface, the membersfully inserted and then twisted to effect a sealed delivery system.Finally, a 0.025 inch exit passageway is drilled into the membercomprising the beneficial agent formulation to provide the manufactureddelivery system.

EXAMPLE 2

A delivery system is manufactured as follows: first, a substantiallyfluid impermeable wall member is prepared by heating pellets of lowdensity polyethylene followed by injection molding the hot polyethyleneinto a tube with an opened end and a closed end. The polyethylene isextruded neat, that is, free of any additions.

Next, a rate controlling wall, shaped as a tube with an opened end and aclosed end, is prepared from a wall forming composition comprising 28 gof cellulose acetate butyrate, 10 g of tributyl citrate and 12 g ofpolymethyl methacrylate. The rate controlling wall is prepared by slowlyadding 12 g polymethyl methacrylate to a heated mixer, 170° C., andmixed for about 5 minutes to allow the polymer crystals to fusetogether. Next, several drops of the tributyl citrate plasticizer areadded to the mixer. Then, about 5 g of the tributyl citrate is added to28 g of cellulose acetate butyrate and the two ingedients mixedthoroughly into a homogeneous mixture. Next, the remainder of thetributyl citrate is added slowly to the polymethyl methacrylate,tributyl citrate in the mixer and the temperature of the mixer islowered to 135° C. Next, the cellulose acetate butyrate, tributylcitrate blend is added to the mixer and the temperature raised to 190°C., to uniformly melt the cellulose acetate butyrate. After 5 minutes atthis temperature, the temperature of the mixer is lowered to 100° C. andthe mixing continued for 5 additional minutes. The mixer was cooled toroom temperature and the rate controlled wall forming composition cutinto small pieces.

Then, the cut wall forming composition is fed into a turning extruder,about 8 rpm, and forced through the core passageway of the extruder. Thecomposition melts at the temperature of the extruder and its die, about140° C. to 150° C. The resultant rate controlling wall tubing measuredabout 0.176 inch outer diameter, 0.156 inch inside diameter, with a wallthickness of about 10 mils (0.256 mm). Then, one end of the tube issealed with a cellulose acetate plug with a drop of adhesive to providea rate controlling wall that surrounds a compartment with an opened endand a closed end.

Next, a driving member composition is prepared from a compositioncomprising 670 g of sodium Carbomer®, the sodium salt of polyacrylicacid, 290 g of sodium chloride, 40 g of polyvinyl pyrrolidone and 10 gof magnesium stearate by wet granulating with denatured ethanol in a90:10 ratio in deionized water. Approximately 700 ml of granulationsolvent is used for the wet granulation. Next, the wet granulation ispassed through a ten mesh screen and placed in a 50° C. oven and driedover night. After drying the granulation is removed from the oven andallowed to hydrate to approximately 9.3% water content. The gradulationis passed again through a 10 mesh screen. After granulation 10.1 g ofmagnesium stearate is added and all the ingredients mixed for about 5minutes. The resulting granulation is ready for use in the deliverydevice.

Then, 96 mg of the driving member composition is weighted and compressedin a Carver® laboratory press. The composition is pressed with a 5/32inch round die and punched with one end flat and the other end concave.The compressed composition is inserted into one end of the ratecontrolling member with the dome flush with the end of the wall.

Next, about 100 g of microcrystalline wax that forms the interface layerbetween the driving member composition and the beneficial agentcomposition is melted in a 72° C. forced air oven to a molten state.Then, 10 cc of a glass syringe is filled with the molten wax and a layer1.25 cm is deposited at the interface of the driving member composition.The wax is allowed to cool to room temperature.

Next, the wall member comprising the substantially impermeable polymeris filled with a beneficial agent formulation. The formulation isprepared by adding 20.58 g of glycerol into a beaker and 0.42 g ofporcine gelatin added to the glycerol. The two ingredients are stirredfor about 1/2 hour at room temperature. Then, an amino acid and, inanother manufacture, a surfactant is added and the mixture heated at60°-70° with constant stirring to yield a uniform blend. The heating andmixing are continued for about 1/2 hour. Finally, the mixture is allowedto cool to room temperature.

Then, 13.3 g of the freshly prepared composition is added to 5.7 g ofporcine somatotropin and blended with a spatula. The somatotropinhormone is added in small increments and blended to yield the hormoneformulation. The hormone formulation is injected into the receivinghousing to fill the member. Next, the first substantially fluidimpermeable member and the second rate controlling member are broughtinto contact at their open ends and heat sealed to form a closedcompartment. Finally, an exit passageway is drilled through the wall forconnecting the exterior of the delivery device with the beneficialhormone formulation for its delivery to an animal.

EXAMPLE 3

A delivery system for delivering a beneficial agent is preparedcomprising (a) a first cylinder shaped housing member comprising a nylonwall that exhibits a low permeability to fluid and surrounds an internalreservoir; and, a second cylinder shaped housing member comprising acellulose acetate having an acetyl content of 38.3% wall that surroundsan internal reservoir. The open ends of each member are joined into anintegral delivery system. The union is effected by enlarging the end ofthe first member for slidably, receiving the end of the second member inmated relation to form an essentially fluid tight union. In anotherembodiment, at least one of the ends of the first member or the secondmember is made smaller than the other end and the smaller end placed inthe non-enlarged end to form a closed delivery system. The respectivemembers are filled prior to telescoping them lengthwise into amanufactured deliverd system. An exit passageway is laser drilledthrough the wall of the first member for delivering a beneficial agentformulation from the delivery system.

The first housing member, in one manufacture, is charged with adispensable formulation comprising a protein such as a hormone likeinsulin, a polyol such as glycerol that increases its solubility inwater without affecting its biological activity, buffered sodium acetatewater and polysorbate-80, a sorbitan monooleate polyoxyethylene. Thesecond housing member comprises a first layer of the sodium salt ofpolyacrylic acid, a middle layer of sodium chloride, a third layer ofthe sodium salt of polyacrylic acid, and a layer of wax at the interfacebetween the beneficial hormone formulation and the layer of the sodiumsalt of polyacrylic polymer.

EXAMPLE 4

The procedure of Example 3 is followed with the conditions as set forth,except that in this example the first housing member formulationcomprises bovine somatotropin dissolved in buffered tris(hydroxymethyl)amino solution comprising the polyols glycerol and erythriol, and thesurfactant sodium lauryl sulfate; and the second housing membercomprises a first compressed layer of the sodium salt of polyacrylicacid, a second compressed layer of the sodium salt of polyacrylic acid,a third compressed layer of the sodium salt of polyacrylic acid, and alayer of the polyolefin polyethylene.

EXAMPLE 5

An embodiment of the invention pertains to a method for delivering abeneficial agent such as a drug to an animal. The method comprisesimplanting a delivery system, shaped, sized and adapted as an implantinto an animal, such as a muscle thereof. The method comprises the stepsof: (A) admitting into an animal a delivery system comprising: (1) ahousing comprising an internal lumen, which housing comprises: (2) afirst wall section comprising a composition that limits the passage offluid into the lumen; (3) a second wall section comprising a compositionthat permits the passage of fluid into the lumen; (4) a beneficial agentformulation in the lumen comprising the first wall section; (5) anexpandable driving composition in the lumen comprising the second wallsection; (6) a layer comprising a composition substantially impermeableto the passage of fluid interposed between the beneficial agentformulation and the driving means; and (7) at least one orifice in thedevice communicating with the lumen; (B) imbibing fluid through the wallfor causing the driving means to expand and push against the beneficialagent formulation; and (C) delivering the beneficial agent formulationfrom the delivery system by the expandable means continuously expandingat a controlled rate thereby causing the beneficial agent formulation tobe delivered in an effective amount through the orifice to the animalover a prolonged period of time.

The novel devices of this invention use means for the obtainment ofprecise release rates in the environment of use while simultaneouslymaintaining the integrity of the device. While there has been describedand pointed out features of the invention as applied to presentlypreferred embodiments, those skilled in the art will appreciate thatvarious modifications, changes, additions and omissions in the devicesillustrated and described can be made without departing from the spiritof the invention.

We claim:
 1. A method for delivering a somatotropin agent to an animal,wherein the method comprises:(a) admitting into the animal a dispensercomprising:(1) a wall that surrounds an internal lumen, said wallcomprising a first section that substantially limits the passage offluid through the wall and a second section that permits the passge offluid through the wall and comprises a pair of ends with one end insidethe other end and held together by a manufacture selected from the groupconsisting of bonding, welding and friction as a means for replacing oneof the sections during use of the dispenser; (2) a somatotropincomposition comprising 5 nanograms to 20 grams in the lumen wherein thefirst section of the wall limits the passage of fluid for substantiallyprotecting the somatotropin from the fluid present in the animal; (3) anosmopolymer composition comprising an expandable hydrogel in the lumeninitially present in the second section of the wall that permits thepassage of fluid; (4) at least one exit passageway in the wall fordelivering the somatotropin from the dispenser; and, (b) delivering tosomatotropin to the animal by the osmopolymer hydrogel imbibing fluidand thereby occupying space in the lumen, for pushing the somatotropinthrough the passageway to the animal.
 2. The method for delivering thesomatotropin to the animal according to claim 1, wherein the animal is apig.
 3. The method for delivering the somatotropin to the animalaccording to claim 1, wherein the somatotropin is porcine somatotropin.4. The method for delivering the somatotropin to the animal according toclaim 1, wherein a partition is between the somatotropin and theosmagent.
 5. A dispenser for delivering a beneficial agent to an animal,the dispenser comprising: a wall surrounding an internal lumen, saidwall comprising a first section that substantially limits the passage offluid through the wall and a second section that permits the passage offluid through the wall; said wall comprising a pair of ends with one endplaced inside the other end, and held together by a manufacture selectedfrom the group consisting of bonding, welding and friction as a meansfor releasably replacing one of the sections during use of thedispenser; a beneficial agent formulation in the lumen comprising apharmaceutically acceptable carrier and from 5 nanograms to 20 grams ofa beneficial agent in the first section for substantially protecting thebeneficial agent from an exterior fluid present in the animal; anosmotic composition comprising 100% in the lumen in the second section,the osmotic composition comprising an osmopolymer for imbibing fluid forincreasing its polymeric volume for displacing the beneficial agentformulation from the first section; and at least one exit passageway inthe dispenser for delivering the beneficial agent to the animal.